The use of oligo-2,6-pyridines as complexing agents that may be incorporated in targeting immunoreagents is disclosed, for example, in WO 92/08494 (PCT/US91/08253).
As discussed in WO 92/08494, these complexing agents solve several problems in the prior art, particularly as regards therapeutic and diagnostic imaging uses of targeting radioactive immunoreagents. The targeting radioactive immunoreagents of that patent application comprise a metal radionuclide ion, a complexing agent, and an immunoreactive group covalently bonded through a protein reactive group to the complexing agent.
The complexing agents of that application have the general structure A-I ##STR1##
wherein
R represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group; PA1 R.sup.1 represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group; PA1 R.sup.2 represents hydroxy, carboxy, hydroxyalkyl, thioalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneiminodiacetic acid, carboxyalkythioalkyl, hydrazinylidenediacetic acid, or a salt of such acids, or two R.sup.2 groups, taken together, represent the atoms necessary to complete a macrocyclic ring structure containing at least one heteroatom coordinating site and at least one, preferably two, alkylene groups forming part of the ring structure; PA1 n is 1, 2, 3 or 4; PA1 o is 0 or 1; PA1 m is 0 or 1; PA1 each R and R.sub.1 is independently selected from hydrogen, alkyl, alkoxy, alkylthio, N,N-dialkylamino, alkylformamido, aryl, heterocyclyl, and a protein reactive group; PA1 each of L.sub.1 and L.sub.2 is a linking group independently selected from a chemical bond, a methylene group (--CH.sub.2 --), and an imino group; PA1 Q is the residue of a chelating group; PA1 each n is independently 1, 2, 3 or 4; and PA1 a is 0 or 1. PA1 hydrogen; PA1 alkyl such as straight or branched chain or cyclic or substituted alkyl, the alkyl portion of which preferably contains from 1 to about 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, 2-ethylhexyl, decyl, hexadecyl, octadecyl, cyclohexyl, cyclopropyl, etc.; PA1 substituted alkyl such as hydroxyalkyl, the alkylene portion of which is a straight or branched chain or cyclic alkylene group, preferably containing from 1 to about 20 carbon atoms, such as methylene, ethylene, propylene, isopropylene, butylene, s-butylene, t-butylene, 2-ethylhexylene, decylene, hexadecylene, octadecylene, cyclohexylene, cyclohexanedimethylene, cyclopropylene, etc.; PA1 substituted alkyl such as alkoxyalkyl, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which is a straight or branched chain or cyclic alkylene group which contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as alkylthioalkyl, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which is a residue of an alkyl group which contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as hydroxyalkylthioalkyl, the alkylene of the hydroxyalkyl portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, the sulfur and oxygen atoms of which are separated by at least two carbon atoms, and the alkylene of the thioalkyl portion of which independently contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as N,N-dialkylaminoalkyl, the alkyl of each of the N,N-alkyl portions of which independently contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as N-hydroxyalkyl-N-alkylaminoalkyl, the alkylene of the N-hydroxyalkyl portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and nitrogen atoms of which are separated by at least two carbon atoms, the alkyl of the N-alkylamino portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as N,N-bis(hydroxyalkyl)-aminoalkyl, the alkylene of each hydroxyalkyl portion of which independently contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and nitrogen atoms of which are separated by at least two carbon atoms, and the alkylene of the aminoalkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as formamidoalkyl, the alkylene portion of which contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 substituted alkyl such as alkylformamidoalkyl, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which contains from 1 to about 20 carbon atoms as described above for alkylene; PA1 alkoxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl; PA1 substituted alkoxy such as hydroxyalkyloxy, the alkylene portion of which is a straight or branched chain or cyclic alkylene group which contains from 2 to about 20 carbon atoms as described above for alkylene, and the oxygen atoms of which are separated by at least two carbon atoms; PA1 substituted alkoxy such as alkoxyalkyloxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, and the oxygen atoms of which are separated by at least two carbon atoms; PA1 substituted alkoxy such as alkylthioalkyloxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, and the oxygen and sulfur atoms of which are separated by at least two carbon atoms; PA1 substituted alkoxy such as hydroxyalkylthioalkyloxy, the alkylene portions of which independently contain from 2 to about 20 carbon atoms as described above for alkylene and the sulfur and oxygen atoms of which are separated by at least two carbon atoms; PA1 alkylthio, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl; PA1 substituted alkylthio such as hydroxyalkylthio, the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, and the oxygen and sulfur atoms of which are separated by at least two carbon atoms; PA1 N,N-dialkylamino, each alkyl portion of which independently contains from 1 to about 20 carbon atoms as described above for alkyl; PA1 substituted N,N-dialkylamino such as N-hydroxyalkyl-N-alkylamino, the alkylene of the N-hydroxyalkyl portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and nitrogen atoms of which are separated by at least two carbon atoms, and the N-alkyl portion of which contains from 1 to about 20 carbon atoms as described for alkyl above; PA1 substituted N,N-dialkylamino such as N,N-bis(hydroxyalkyl)amino, the alkylene of each N-hydroxyalkyl portion of which contains from 2 to about 20 carbon atoms as described above for alkylene and the oxygen and nitrogen atoms of which are separated by at least two carbon atoms; PA1 alkylformamido, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl; PA1 aryl preferably containing from about 6 to 24 carbon atoms such as phenyl, naphthyl, benzopyrenyl, and phenanthryl; PA1 substituted aryl such as alkylaryl wherein the alkyl portion is as defined above and the aryl as defined above, such as tolyl, xylyl, 2-(2,3-dimethoxypropoxy)ethylphenyl, 4-(3-t-butoxypropyl)naphthyl, and ethylphenyl; PA1 substituted aryl such as nitroaryl, wherein the aryl portion as defined above, such as nitrophenyl; PA1 substituted aryl such as cyanoaryl, wherein the aryl portion as defined above, such as cyanonaphthyl and cyanophenyl; PA1 chloro-, bromo-, fluor- and iodo-substituted aryl, wherein the aryl portion as defined above, such as chlorophenyl, iodophenyl, and pentafluorophenyl; PA1 aryl substituted aryl such as arylaryl, wherein each of the aryl portions are independently aryl and may be substituted as defined above, such as biphenyl and 4-[9-(10-methylanthracenyl)]-phenyl; PA1 substituted aryl such as N,N-dialkylaminoaryl, wherein the aryl portion as defined above and the N,N-dialkylamino portion as defined above, such as N-hexadecyl-N-methylaminophenyl and N-methyl-N-octadecylaminophenyl; PA1 substituted aryl such as alkoxyaryl wherein the aryl portion as defined above and the alkyl portion as defined above, such as methoxyphenyl, methylenedioxyphenyl, methoxyethoxyphenyl, dimethoxyphenyl, phenoxyphenyl, 4-methoxy-3-iodophenyl, and 4-methoxy-3-N,N-dimethylphenyl, 4-(2-hydroxyethoxy)phenyl, 5-hydroxypropoxy-3,4-methylenedioxyphenyl, 4-(2-methoxyethoxy)ethylphenyl, and 2-(4-methoxy)napthyl; PA1 substituted aryl such as alkylthioaryl wherein the aryl portion as defined above and the alkyl portion as defined above, such as methylthiophenyl and 4-(2-ethylthio)phenyl; PA1 substituted aryl such as alkylformamidoaryl wherein the aryl portion as defined above and the alkyl portion as defined above, such as N-butylformamidonaphthyl; PA1 substituted aryl such as carboxylaryl, sulfonatoaryl, and hydroxyaryl, wherein the aryl portion as defined above such as hydroxyphenyl, carboxyphenyl, dicarboxyphenyl, hydroxybenzopyrenyl, hydroxyethylphenyl, bis(hydroxymethyl)phenyl, dihydroxycyclohexylphenyl, hydroxymethylanthracenyl, and sulfonatophenyl; PA1 substituted aryl such as alkoxyalkyloxyaryl, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen atoms of which are separated by at least two carbon atoms such as, for example, 4-(2-ethoxyethoxy)phenyl, methoxyethoxynaphthyl, methoxyethoxyphenyl, 3,4-bis(2-methoxyethoxy)phenyl, 4-W-methoxy-poly(ethylene oxidyl)phenyl, the poly(ethylene oxidyl) portion of which contains from 2 to 100 recurring units of ethylene oxide; PA1 substituted aryl such as hydroxyalkylthioaryl, the alkylene portion of which contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and sulfur atoms of which are separated by at least two carbon atoms, and the arylene portion of which contains from 6 to about 24 carbon atoms as described above for arylene, for example, 2-hydroxyethylthiophenyl, 2,3-dihydroxypropylthiophenyl, and 4-(2,3-dihydroxypropyl)thio-3-methoxyphenyl; PA1 substituted aryl such as hydroxyalkylthioalkylaryl, the hydroxyalkylthio portion of which contains an alkylene group having from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and sulfur atoms of which are separated by at least two carbon atoms, the alkylene of the thioalkylaryl portion of which contains from 1 to about 20 carbon atoms as described above for alkylene, and the arylene portion of which contains from 6 to about 24 carbon atoms as described above for arylene, for example, (2-hydroxyethyl)thiomethylphenyl, 2-(2,3-dihydroxypropyl)thioethylphenyl, and 4-[(2,3-dihydroxypropyl)thiomethyl]phenyl; PA1 substituted aryl such as hydroxyalkylthioalkylaryl, the hydroxyalkylthio portion of which contains an alkylene group having from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and sulfur atoms of which are separated by at least two carbon atoms, the alkylene of the thioalkylaryl portion of which contains from 1 to about 20 carbon atoms as described above for alkylene, and the arylene portion of which contains from 6 to about 24 carbon atoms as described above for arylene, for example, (2-hydroxyethyl)thiomethylphenyl, 2-(2,3-dihydroxypropyl)thioethylphenyl, and 4-[(2,3-dihydroxypropyl)thiomethyl]phenyl; PA1 hydroxyalkylthioalkyloxyaryl, each alkylene portion of which independently contains from 2 to about 20 carbon atoms as described above for alkylene, the oxygen and sulfur atoms of which are separated by at least two carbon atoms, and the arylene portion of which contains from 6 to about 24 carbon atoms as described above for arylene, for example, 4-[2-(2-hydroxyethyl)thioethoxy]phenyl, and 4,5-bis[2-(2-hydroxyethyl)thioethoxy]naphthyl; PA1 aryloxy, the aryl portion of which contains from 6 to about 24 carbon atoms as described above for aryl, which aryl may be substituted as described above, such as phenoxy, nitrophenoxy, bromophenoxy, biphenyloxy, carboxyphenoxy, and sulfonatophenoxy; PA1 substituted alkyl such as aralkyl, the alkylene portion of which contains from 1 to about 20 carbon atoms as described above for alkylene and the aryl portion of which contains from about 6 to 24 carbon atoms as described above for aryl, for example, benzyl, benzhydryl, trimethylbenzyl; and 9-(10-methyl)anthracenyl; PA1 substituted aralkyloxy, the alkylene portion of which contains from 1 to about 20 carbon atoms as described above for alkylene, and the aryl portion of which contains from about 6 to 24 carbon atoms as described above for aryl, for example, benzyloxy, methylenedioxybenzyloxy, 2-(methylenedioxyphenyl)ethoxy and phenylethoxy; PA1 substituted alkyl such as alkoxyaralkyl, the alkylene portion of which contains from 1 to about 20 carbon atoms as described for alkylene above, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the arylene portion of which contains from about 6 to 24 carbon atoms as described above for arylene, for example, 3-(2,3-dimethoxypropoxy)benzyl, methoxybenzyl, and 4-poly(ethylene oxidyl)benzyl, the poly(ethylene oxidyl) portion of which contains from 2 to 100 recurring units of ethylene oxide; PA1 substituted alkyloxy such as alkoxyaralkyloxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, the alkylene portion of which contains from 1 to about 20 carbon atoms as described above for alkylene, and the arylene portion of which contains from about 6 to 24 carbon atoms as described above for arylene, for example, 3-(2,3-dimethoxypropoxy)benzyloxy, methoxybenzyloxy, and 4-W-methoxy-poly(ethylene oxidyl)benzyloxy, the poly(ethylene oxidyl) portion of which contains from 2 to 100 recurring units of ethylene oxide; PA1 substituted aryloxy such as alkylaryloxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the arylene portion of which contains from about 6 to 24 carbon atoms as described above for arylene, for example, methylphenoxy, cyclohexylphenoxy, and butylphenoxy; PA1 substituted alkyloxy such as alkoxyaryloxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described above for alkyl, and the arylene portion of which contains from about 6 to 24 carbon atoms as described above for arylene, for example, methoxyphenoxy and 4-poly(ethylene oxidyl)phenoxy, the poly(ethylene oxidyl) portion of which contains from 2 to 100 recurring units of ethylene oxide; PA1 substituted or unsubstituted heterocyclyl, containing from 5 to about 36 total nuclear carbon and heteroatoms and preferably comprising one ore more rings comprised of 5 or 6 nuclear carbon and heteroatoms such as N, S, P or 0, for example, pyridyl, methylpyridyl, N-morpholino, dimethylaminopyridyl, methoxypropylpyridyl, oxazolyl, imidazolyl, pyrazolyl, quinolyl, thiazinyl, furanyl, pyranyl, and dimethylphosphazinyl; PA1 substituted alkyl group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted alkoxy group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted alkylthio group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted N,N-dialkylamino group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted alkylformamido group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted aryl group containing a protein reactive group, which protein reactive group is defined hereinbelow; PA1 substituted heterocyclyl group containing a protein reactive group, which protein reactive group is defined hereinbelow; and, PA1 a protein reactive group as defined hereinbelow. PA1 a chemical bond; PA1 an imino group such as --NR"--, wherein R" is selected from a group consisting of hydrogen, an alkyl group as described above, and the residue of a chelating group as described below. Preferably, R" is a hydrogen or a methyl group. PA1 Each n in structure I is independently 1, 2, 3 or 4; and, PA1 a is 0 or 1. PA1 (a) by cleavage of one or more chemical bonds comprising an antibody, said bonds being selected from, for example, carbon-nitrogen bonds, sulfur-sulfur bonds, carbon-carbon bonds, carbon-sulfur bonds, and carbon-oxygen bonds, and wherein the method of said cleavage is selected from: PA1 (b) by formation of one or more chemical bonds between one or more reactants, such as formation of one or more covalent bonds selected from, for example, carbon-nitrogen bonds (such as, for example, amide bonds, amine bonds, hydrazone bonds, and thiourea bonds), sulfur-sulfur bonds such as disulfide bonds, carbon-carbon bonds, carbon-sulfur bonds, and carbon-oxygen bonds, and employing as reactants in said chemical bond formation one or more reagents comprising amino acids, peptides, carbohydrates, linking groups as defined herein, spacing groups as defined herein, protein reactive groups as defined herein, and antibody fragments such as are produced as described in (a), above; or, PA1 (c) by formation of one or more non-covalent "bonds" between one or more reactants or components such as, for example, (i) non-covalent hydrophobic interactions (or "bonds") which occur in a polar medium (such as an aqueous medium) between chemical species that each independently comprise mutually accessible regions of low polarity (such as regions containing aliphatic hydrocarbon and carbocyclic groups), and (ii) non-covalent hydrogen "bond" interactions such as occur in the interaction of an oligonucleotide with a complementary oligonucleotide; or PA1 (d) by the well known methods of molecular biology and genetic engineering of antibody genes, for example, in the genetic engineering of a single chain immunoreactive group or a Fv fragment through manipulation of DNA sequence coding. PA1 (1) a group that will react directly with amine, alcohol, or sulfhydryl groups on the immunoreactive protein or biological molecule containing the reactive group, for example, active halogen containing groups including, for example, chloromethylphenyl groups and chloroacetyl (ClCH2C(.dbd.O)--] groups, activated 2-(leaving group substituted)-ethylsulfonyl and ethylcarbonyl groups such as 2-chloroethylsulfonyl and 2-chloroethylcarbonyl; vinylsulfonyl; vinylcarbonyl; epoxy; isocyanato; isothiocyanato; aldehyde; aziridine; succinimidoxycarbonyl; activated acyl groups such as carboxylic acid halides; mixed anhydrides and the like; and other groups known to be useful in conventional photographic gelatin hardening agents; PA1 (2) a group that can react readily with modified proteins or biological molecules containing the immunoreactive group, i.e., proteins or biological molecules containing the immunoreactive group modified to contain reactive groups such as those mentioned in (1) above, for example, by oxidation of the protein to an aldehyde or a carboxylic acid, in which case the "linking group" can be derived from protein reactive groups selected from amino, alkylamino, arylamino, hydrazino, alkylhydrazino, arylhydrazino, carbazido, semicarbazido, thiocarbazido, thiosemicarbazido, sulfhydryl, sulfhydrylalkyl, sulfhydrylaryl, hydroxy, carboxy, carboxyalkyl and carboxyaryl. The alkyl portions of said linking groups can contain from 1 to about 20 carbon atoms. The aryl portions of said linking groups can contain from about 6 to about 20 carbon atoms; and PA1 (3) a group that can be linked to the protein or biological molecule containing the immunoreactive group, or to the modified protein as noted in (1) and (2) above by use of a crosslinking agent. The residues of certain useful crosslinking agents, such as, for example, homobifunctional and heterobifunctional gelatin hardeners, bisepoxides, and bisisocyanates can become a part of a linking group during the crosslinking reaction. Other useful crosslinking agents, however, can facilitate the crosslinking, for example, as consumable catalysts, and are not present in the final conjugate. Examples of such crosslinking agents are carbodiimide and carbamoylonium crosslinking agents as disclosed in U.S. Pat. No. 4,421,847 and the ethers of U.S. Pat. No. 4,877,724. With these crosslinking agents, one of the reactants such as an immunoreactive group must have a carboxyl group and the other such as the chelating agent of this invention must have a reactive amine, alcohol, or sulfhydryl group. In amide bond formation, the crosslinking agent first reacts selectively with the carboxyl group, then is split out during reaction of the thus "activated" carboxyl group with an amine to form an amide linkage between the immunoreactive group and the chelating agent and thus covalently bonding the two moieties. An advantage of this approach is that crosslinking of like molecules is avoided, whereas the reaction of, for example, homo-bifunctional crosslinking agents is nonselective and unwanted crosslinked molecules are obtained.
R.sup.3 represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group;
R.sup.4 represents hydrogen or a protein reactive group;
provided that at least one of n and m is 0 and at least one of R, R.sup.1, R.sup.3 and R.sup.4 is a protein reactive group.
While a significant advance over the prior art, one limitation regarding those oligo-2,6-pyridine chelators of structure A-I which contain 3, 4, 5, or 6 pyridine rings is their requirement of substitution by R.sup.2 at both the 6-position of the first pyridine ring and the respective 6"-, 6"', 6""- and 6""'-positions of the third, fourth, fifth, and sixth pyridine ring. In the synthesis of these compounds, each R.sup.2 substitutent requires at least one chemical reaction to occur at some point in the synthetic sequence at both the 6-position of the first pyridine ring and at the respective 6"-, 6"', 6""- and 6""'-positions of the third, fourth, fifth, and sixth pyridine ring of the oligo-2,6-pyridines, and the overall yield of the oligo-2,6-pyridine chelator comprises the arithmetical product of the yield of the reaction to generate the appropriate R.sup.2 at each of the two reaction sites. This yield is necessarily reduced to less than 100% when one of the reactions involving introduction and/or modification of the substituent at the 6-position and the substituents at the respective 6"-, 6"', 6""- and 6""'-positions is less than 100%, as is most often the case.
Furthermore, in those non-macrocyclic oligo-2,6-pyridine chelators of structure A-I which contain 3, 4, 5, or 6 pyridine rings, wherein each R.sup.2 represents hydroxy, carboxy, hydroxyalkyl, thioalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneimino-diacetic acid, carboxyalkythioalkyl, hydrazinylidenediacetic acid, or a salt of such acids, the capacity of a given chelator to bind with a high binding constant to a given metal ion of a fixed charge is limited by conformational energies attainable by the oligo-2,6-pyridine molecular geometry. The molecular geometry and conformational strain energies impose a limit to the amount of interpyridine bond angle bending that can occur in the oligo-2,6-pyridine component. In an s-cis configuration, the restrictions in the interpyridine bond angle bending in the oligo-2,6-pyridine component limit the extent to which the two R.sup.2 groups can approach one another and participate with the oligo-2,6-pyridine nitrogens in the chelation of a metal ion. Consequently, the configuration that the chelating moiety can achieve about a metal ion can be limited with respect to attainment of rapid kinetics of metal binding and large binding constant between the chelator and the metal than can be achieved with a chelating oligo-2,6-pyridine that is not constrained by the interpyridine bond energies.
With respect to chelated radioisotopes by the oligo-2,6-pyridines disclosed in WO 92/08494 and incorporated in targeting immunoreagents (radioimmunoconjugates) which comprise an immunoreactive agent, a chelating group and a metal ion, it is advantageous to be able to detect the accumulation of said radioimmunoconjugate at a tumor site so as to be able to better monitor the course of treatment of a patient with said radioimmunoconjugate. Few metal ion radioisotopes have properties which are optimally suited for both diagnostic imaging and for therapeutic applications. As such it is often necessary to use two different metal ions such as, for example, .sup.111 In.sup.+3 for diagnostic imaging purposes and such as, for example, .sup.90 Y.sup.+3 for therapeutic purposes in the above application. Because these metal ions have different sizes and chelate binding requirements, and although the oligo-2,6-pyridines disclosed in WO 92/08494 bind these metal ions rapidly and hold them tenaciously, there is still a limit to the respective binding rates and binding constants that is imposed by the disubstituted nature of the oligo-2,6-pyridines outlined above.
It is, therefore, desireable to have oligo-2,6-pyridine chelating agents that are not limited in their ability to bind a metal ion because of restrictions imposed by the interpyridine binding energetics and which oligo-2,6-pyridine chelating agents are capable of binding both a diagnostic imaging isotope and a therapeutic isotope rapidly and with a high binding constant.